title: Substrate/propeptide-derived endo-epoxysuccinyl peptides as highly potent and selective cathepsin B inhibitors.
abstract: Based on recent information about the anti-substrate binding mode of the propeptide portion of procathepsin B and the well established substrate-like binding of epoxysuccinyl-dipeptide carboxylates to the S' subsites of cathepsin B a new endo-trans-epoxysuccinyl peptide was synthesized that contains the dipeptide moiety Leu-Pro-OH for the P1'-P2' substrate positions and the tripeptide moiety Leu-Gly-Gly-OMe (sequence portion 46-48 of the propeptide) for the P2-P4 positions in anti-substrate orientation. With an unequivocal (2S,3S) configuration this new trans-epoxysuccinyl peptide derivative was found to inhibit cathepsin B with an apparent second-order rate constant of 1,520,000 M(-1) s(-1) which represents so far the most potent inhibitor among E-64-derived compounds. Conversely, the (2R,3R) diastereomer exhibited a significantly lower inhibition potency. This observation fully agrees with our previous findings that inhibitor/enzyme interactions at the S subsites are favored by the (2S,3S) and reverse interactions at the S' subsites by the (2R,3R) configuration of the trans-epoxysuccinyl moiety.
authors.affiliation: Max-Planck-Institut für Biochemie, Martinsried, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Schaschke
authors.forename: I
authors.initials: I
authors.lastname: Assfalg-Machleidt
authors.forename: W
authors.initials: W
authors.lastname: Machleidt
authors.forename: L
authors.initials: L
authors.lastname: Moroder
mesh_terms: D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D006801:Humans; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010206:Papain / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; D010206:Papain